Among those chemotherapeutic compounds known to possess antitumor activity in mammalian systems is adriamycin, which has the molecular structure shown below. ##STR1##
The pharmacological effectiveness of many drugs is greatly enhanced when they are released continuously over an extended time in subject animals in contrast to when the same drugs are administered all at once or in several discrete doses.
One of the methods by which drugs may be slowly released in subject animals is to microencapsulate the drugs within suitable biocompatible vehicles that allow drugs to slowly leak through the vehicle boundaries.
Lipid vesicles, or liposomes, have been found to be one type of drug delivery vehicle which can be used to microencapsulate various chemotherapeutics. However, liposomes suffer from the following defects. The timed released fo chemotherapeutics through lipid vesicle membranes are often difficult to control and to vary in an easily selectable manner. Some of the lipids employed in liposome drug carriers are difficult to synthesize and therefore expensive. Liposomes also have limited stability and considerable nonuniformity. Many types of lipids are not well tolerated by mammals.
In contrast to the use of lipids as the main constituent of drug delivery vehicles, polyamino acids offer several potential advantages. Polyamino acids are inexpensive, readily available in large quantities, and are readily compatible with biological systems.
It was discovered previously that thermal peptides and proteins can be made simply by heating amino acids together in a flask for several hours (Fox et al., 1958). Such compounds and methods for their preparation are described in U.S. Pat. Nos. 3,052,655 and 3,076,790, by Fox et al.
Thermal copolyamino acids form a class of thermally engineered proteins because they possess amino acid sequence that have not been currently found in nature. They sometimes are referred to as proteinoids to reflect the fact that, although they resemble proteins structurally and functionally, they are produced abiotically in contrast to biologically generated proteins such as hemoglobin, to use just one example. They are also referred to as thermal proteins for the same reason. Organisms do not make protein by heating amino acids.
Thermally engineered proteins, or proteinoids, are much easier to manufacture than proteins which are engineered by genetic means or by standard organic synthetic means.
It was previously found that thermal copolyamino acids, upon being heated in aqueous solution and allowed to cool, spontaneously form microspheres or microcapsules approximately one micron in size (Fox, 1960).
The object of this invention was to employ thermal copolyamino acids as a vehicle for the microencapsulation and in vivo delivery of a chemotherapeutic compound.